CN114642669B - Senkyunolide I compound and application thereof in preparation of medicines treating thrombus diseases - Google Patents
Senkyunolide I compound and application thereof in preparation of medicines treating thrombus diseases Download PDFInfo
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- CN114642669B CN114642669B CN202011508557.8A CN202011508557A CN114642669B CN 114642669 B CN114642669 B CN 114642669B CN 202011508557 A CN202011508557 A CN 202011508557A CN 114642669 B CN114642669 B CN 114642669B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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Abstract
The invention discloses a senkyunolide I compound and application thereof in preparing medicaments for treating thrombus diseases, and the application of senkyunolide I and cryptotanshinone in combination can inhibit thrombus formation, thereby defining a novel action path and a novel treatment mechanism of the senkyunolide I and cryptotanshinone in combination for treating thrombus diseases and cardiovascular diseases caused by thrombus; provides a basis for the clinical application of the combination of the senkyunolide I and the cryptotanshinone.
Description
Field of the art
The invention relates to the technical field of medicines, in particular to application of senkyunolide I and cryptotanshinone in preparing medicines for treating thrombus diseases.
(II) background art
The diseases caused by two pathological processes of thrombosis and thromboembolism are called thrombotic diseases, seriously endanger the health of human beings, shorten the survival time of patients and influence the survival quality of patients. World health organization researches show that middle-aged and elderly people are high incidence people of thrombotic diseases, and the world is up to 1200 ten thousand people each year dead from thrombus-induced cardiovascular and cerebrovascular diseases. Thrombosis is a multifactorial process of change that is mediated by a set of genetic and environmental factors that interact. Clinically common thrombotic patients, the most prominent features are familial genetics, recurrent attacks, symptom severity, abnormality of the thrombotic site, and time-to-onset rejuvenation.
In the development of novel drugs and drug targets for treating thrombotic diseases, natural plants are one of the most important sources. The traditional Chinese medicine is an important part of the plant medicine treasury, so that the search for new antithrombotic medicines in the traditional Chinese medicine is particularly important.
The senkyunolide I (senkynolide I) is a phthalide compound separated from traditional Chinese medicine extracts such as ligusticum wallichii, angelica and the like, has good fat solubility and water solubility, can rapidly enter blood and cerebrospinal fluid, and has the potential of developing new medicines. The pharmacological actions mainly comprise: can relieve ConA induced erythrocyte deformability injury and reduce aggregation; inhibiting calcium influx of guinea pig cardiomyocytes and human neuroblastoma; reduce NO in brainstem of animal model with ischemia reperfusion, and inhibit activity of NO synthase.
Cryptotanshinone (CTS) is the main fat-soluble extract of red sage root, and takes the form of orange needle-like crystals. The diterpenoid quinone compound belongs to diterpenoid quinone compounds, and most of the components have ternary or quaternary ring o-quinone or p-quinone structures on the skeleton, so that the diterpenoid quinone compound has the activities of resisting tumors, resisting oxidation, resisting inflammation, resisting bacteria and the like. Cryptotanshinone is one of main pharmacological active substances of the red sage root, and the unique chemical structure and pharmacokinetic properties of cryptotanshinone make cryptotanshinone a target of attention. Recent researches prove that the composition has good application prospect in the aspects of cardiovascular diseases, anti-tumor, antibacterial and anti-inflammatory, metabolic disorder diseases, neurodegenerative diseases and the like.
(III) summary of the invention
The invention aims to provide a senkyunolide I compound and application thereof in preparing medicines for treating thrombus diseases. The senkyunolide I compound can inhibit thrombosis, thereby treating thrombosis and cardiovascular related diseases caused by thrombosis.
The technical scheme adopted by the invention is as follows:
the invention provides a senkyunolide I compound, which is formed by mixing senkyunolide I and cryptotanshinone.
Further, preferably, the senkyunolide I complex is prepared from senkyunolide I and cryptotanshinone in a mass ratio of not less than 50: 1.
Further, preferably, the senkyunolide I compound is prepared from senkyunolide I and cryptotanshinone in a mass ratio of 50-100: 1.
Further, preferably, the senkyunolide I compound is prepared from senkyunolide I and cryptotanshinone in a mass ratio of 50: 1.
The invention also provides an application of the senkyunolide I compound in preparing a medicine for treating thrombus diseases.
Further, the thrombotic diseases include atherosclerosis, hypertension, myocardial infarction, heart failure, etc. caused by thrombosis.
The medicine for treating thrombus disease also comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, such as a filler, an adhesive, a wetting agent, an absorption enhancer, a surfactant and the like. In addition, other adjuvants such as flavoring agent, sweetener, etc. can be added.
The dosage form of the medicine for treating the thrombus disease can be tablets, pills, powder, dispersible tablets, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, soft capsules, hard capsules, sterile injection, liniments or suppositories; can be made into conventional, quick-release, slow-release or delayed-release preparation.
The medicaments of the present invention may also be administered by a variety of routes including: oral, nasal, intramuscular, subcutaneous, intravenous, and the like.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides an application of combination of senkyunolide I and cryptotanshinone in preparing a medicine for treating thrombus diseases, which can obviously inhibit thrombus formation and provides a basis for clinical medicine of combination of senkyunolide I and cryptotanshinone.
(IV) description of the drawings
Fig. 1: chemical structure of senkyunolide I and cryptotanshinone.
Fig. 2: example 1 fluorescence image, 50 μg/ml senkyunolide I,1 μg/ml cryptotanshinone alone and in combination in red blood cell fluorescence labeled zebra fish thrombus model can significantly inhibit thrombus formation.
Fig. 3: quantitative analysis chart of example 1. Based on the quantitative analysis of fluorescence dynamic imaging data, the combination of the senkyunolide I (50 mug/ml) and the cryptotanshinone (1 ug/ml) has obviously better effect than the single use, and the statistical analysis proves that the senkyunolide I and the cryptotanshinone have synergistic effect. There was a statistical difference between groups labeled with different letters.
Fig. 4: example 2 quantitative analysis of the inhibition effect of different monomer combinations on the zebra fish thrombus model. The antithrombotic effect of the monomer compounds of the red sage root and the ligusticum wallichii suggests that senkyunolide I (50 mug/ml) and 1 mug/ml cryptotanshinone have obvious antithrombotic effect, but the compatibility of senkyunolide I (50 mug/ml) and salvianolic acid B (50 mug/ml) has no obvious therapeutic effect on rosmarinic acid (50 mug/ml) and tanshinol (50 mug/ml). There was a statistical difference between groups labeled with different letters.
Fig. 5: example 3 quantitative analysis chart of inhibition effect of combination of senkyunolide I and cryptotanshinone on zebra fish thrombus model with different ratio concentrations. It is suggested that 50. Mu.g/ml senkyunolide I and 1. Mu.g/ml cryptotanshinone have synergistic effect, and that 100. Mu.g/ml senkyunolide I and 1. Mu.g/ml cryptotanshinone have no difference in therapeutic effect. There is no synergistic effect between the combination of 10 μg/ml senkyunolide I and 1 μg/ml cryptotanshinone and the combination of 20 μg/ml senkyunolide I and 1 μg/ml cryptotanshinone. There was a statistical difference between groups labeled with different letters.
(fifth) detailed description of the invention
The invention will be further described with reference to the following specific examples, but the scope of the invention is not limited thereto:
example 1
1. Experimental materials
Phenylhydrazine, available from Shanghai Ala Biochemical technologies Co., ltd
Transparent 96-well cell culture plates, available from NEST company
E3 buffer: every 1000L deionized water contains NaCl 292.5g,KCl 12.67g,CaCl 2 36.63g and MgSO 4 39.6g, the pH was adjusted to 7.2 with 1M aqueous sodium bicarbonate.
Juvenile fish culture solution: e3 buffer containing 200. Mu.M 1-phenyl-2-thiourea (PTU) was used to inhibit melanin formation for subsequent experimental observation.
Transgenic zebra fish Tg (LCR: eGFP) of red blood cells marked by green fluorescent protein is purchased from a zebra fish split platform of the university of Zhejiang public technical platform.
2. Experiment
Grouping of drugs: the volume concentration of the medicines is 0.1% DMSO control group, 1 mug/ml of cryptotanshinone, 50 mug/ml of senkyunolide I,1 mug/ml of cryptotanshinone and 50 mug/ml of senkyunolide I, and the medicines with corresponding final concentrations are prepared by taking juvenile fish culture solution as a solvent in each group.
Experiment: the transgenic zebra fish Tg (LCR: eGFP) embryo of the red blood cells marked by the green fluorescent protein is collected into a 10cm culture dish, 30mL of E3 buffer containing 0.1mg/L methylene blue is added, and after standing for 12 hours at 28 ℃, the liquid is changed into a juvenile fish culture liquid so as to inhibit melanin generation. Culturing at 28deg.C for 2 days, transferring embryos to 24-well plates, adding 10-12 embryos per well, adding 2ml of different medicines diluted with juvenile fish culture solution, standing at room temperature for protection for 24 hours, washing embryos 3 times with juvenile fish culture solution, adding mould-making medicine Phenylhydrazine (PHZ) diluted to 0.75 μm with juvenile fish culture solution, standing at 28deg.C for 12 hours, washing embryos 3 times with juvenile fish culture solution again, changing into 1mL E3 buffer per well, taking out juvenile fish, anesthetizing with anesthetic, placing into 96-well plates at a ratio of one per well, and automatically shooting with a Mocha camera. Each well was photographed at a speed of 100 frames/second. After shooting, the back aorta and tail vein sites of the same part of each zebra fish embryo are selected for observation, and the machine automatically calculates the number of red blood cells flowing through the sites in unit time.
3. Conclusion: FIG. 2 shows that 50ug/ml of senkyunolide I and 1ug/ml of cryptotanshinone have remarkable inhibitory effect on phenylhydrazine-induced zebra fish thrombus model, and are superior to the effects of 50ug/ml of senkyunolide I or 1ug/ml of cryptotanshinone alone.
The statistics in example 1 were normalized to the number of red blood cells in each group, and the calculated synergy index found the same as the results in example 1: the combination of 50ug/ml of senkyunolide I and 1ug/ml of cryptotanshinone has remarkable inhibition effect on phenylhydrazine-induced zebra fish thrombus model, and has better effect than that of single 50ug/ml of senkyunolide I or 1ug/ml of cryptotanshinone, has statistical difference, and the synergy index of drug effect is 0.7679. The data provides a theoretical basis for the combination of the dose of the monomer medicament for treating thrombosis and cardiovascular diseases (figure 3).
Example 2:
the drugs of each group of example 1 were changed to: a DMSO control group of 0.1%, salvianolic acid B50 μg/ml group, salvianic acid A50 μg/ml group, rosmarinic acid 50 μg/ml group, cryptotanshinone 1 μg/ml group, ferulic acid 25 μg/ml group, senkyunolide I50 μg/ml group, ferulic acid 25 μg/ml+rosmarinic acid 50 μg/ml group, ferulic acid 25 μg/ml+salvianic acid 50 μg/ml group, senkyunolide I50 μg/ml+rosmarinic acid 50 μg/ml group, senkyunolide I50 μg/ml+salvianic acid 50 μg/ml group, senkyunolide I50 μg/ml+salvianolic acid B50 μg/ml group were prepared, and the results are shown in FIG. 4. FIG. 4 shows that in addition to senkyunolide I (50 ug/ml) and cryptotanshinone (1 ug/ml) in example 1, the main compounds salvianolic acid B (50 ug/ml), salvianic acid (50 ug/ml), rosmarinic acid (50 ug/ml) and ferulic acid (25 ug/ml) in the medicinal materials were detected simultaneously, and only the single administration of senkyunolide I (50 ug/ml) and cryptotanshinone (1 ug/ml) was found to have a remarkable inhibitory effect on thrombus. Further, the compatibility of the monomers is detected, and no synergy is found.
Example 3
The drugs of each group of example 1 were changed to: a control group of 0.1% DMSO, 1. Mu.g/ml of cryptotanshinone, 50. Mu.g/ml of senkyunolide, 1. Mu.g/ml of cryptotanshinone, 10. Mu.g/ml of senkyunolide, 1. Mu.g/ml of cryptotanshinone, 25. Mu.g/ml of senkyunolide, 1. Mu.g/ml of cryptotanshinone, 50. Mu.g/ml of senkyunolide, 1. Mu.g/ml of cryptotanshinone, and 100. Mu.g/ml of senkyunolide were prepared, and the results were shown in FIG. 5. FIG. 5 shows the detection of the compatible concentrations of senkyunolide I and cryptotanshinone. The concentrations (50. Mu.g/ml) of senkyunolide I in example 1 were changed to 100. Mu.g/ml, 25. Mu.g/ml and 10. Mu.g/ml, and the effect of senkyunolide I and cryptotanshinone in combination at different concentrations was examined in antithrombotic, suggesting that the combination of 50. Mu.g/ml senkyunolide I and 1. Mu.g/ml cryptotanshinone and the combination of 100. Mu.g/ml senkyunolide I and 1. Mu.g/ml cryptotanshinone have synergistic effects, but the efficacy of both groups is not different. There is no synergistic effect between the combination of 10 μg/ml senkyunolide I and 1 μg/ml cryptotanshinone and the combination of 25 μg/ml senkyunolide I and 1 μg/ml cryptotanshinone.
Claims (2)
1. A senkyunolide I compound for treating thrombus diseases is characterized in that the senkyunolide I compound is prepared from senkyunolide I and cryptotanshinone in a mass ratio of 50-100: 1.
2. The senkyunolide I complex as claimed in claim 1, wherein the senkyunolide I complex comprises senkyunolide I and cryptotanshinone in a mass ratio of 50: 1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555834A (en) * | 2003-12-31 | 2004-12-22 | 广州安健实业发展有限公司 | Medicinal composition containing salvia root effective component and ligusticum effecive component and its preparation |
| CN1742793A (en) * | 2004-09-02 | 2006-03-08 | 山东绿叶天然药物研究开发有限公司 | Medicine composition and use thereof |
| WO2007106049A1 (en) * | 2006-03-16 | 2007-09-20 | Moleac Pte Ltd | Combination therapy for treatment of patients with neurological disorders and cerebral infarction |
| CN102144998A (en) * | 2010-02-09 | 2011-08-10 | 上海张江中药现代制剂技术工程研究中心 | Application of senkyunolide I to medicaments for prevention and treatment of cerebral apoplexy and relevant treatment during convalescence |
| CN111419900A (en) * | 2020-05-20 | 2020-07-17 | 西南大学 | Improved nano suspension freeze-dried preparation based on perhexiline and preparation method thereof |
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- 2020-12-18 CN CN202011508557.8A patent/CN114642669B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1555834A (en) * | 2003-12-31 | 2004-12-22 | 广州安健实业发展有限公司 | Medicinal composition containing salvia root effective component and ligusticum effecive component and its preparation |
| CN1742793A (en) * | 2004-09-02 | 2006-03-08 | 山东绿叶天然药物研究开发有限公司 | Medicine composition and use thereof |
| WO2007106049A1 (en) * | 2006-03-16 | 2007-09-20 | Moleac Pte Ltd | Combination therapy for treatment of patients with neurological disorders and cerebral infarction |
| CN102144998A (en) * | 2010-02-09 | 2011-08-10 | 上海张江中药现代制剂技术工程研究中心 | Application of senkyunolide I to medicaments for prevention and treatment of cerebral apoplexy and relevant treatment during convalescence |
| CN111419900A (en) * | 2020-05-20 | 2020-07-17 | 西南大学 | Improved nano suspension freeze-dried preparation based on perhexiline and preparation method thereof |
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